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PHL 424
Antimicrobials
2nd Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Inhibitors of bacterial protein synthesis,
Tetracyclines
 Tetracyclines are safe, inexpensive broadspectrum bacteriostatic antibiotics that
inhibit protein synthesis
 The basic tetracycline structure consists of
four benzene rings with various substituent
on each ring (C22H24N2O8; M.Wt. 444.43)
Inhibitors of bacterial protein synthesis,
Tetracyclines
 Tetracyclines are classified as:
1. Short-acting: This includes
oxytetracycline (a natural product
produced by Streptomyces rimosus) &
tetracycline (a semisynthetic derivative of
chlortetracycline, produced by
Streptomyces aureofaciens
2. Intermediate acting: This includes
demeclocycline (the product of a mutant
strain of Strep. Aureofaciens) and
methacycline (semisynthetic)
3. Long-acting, e.g., doxycycline and
minocycline which are semisynthetic
derivatives
 The almost complete absorption and slow excretion of doxycycline and minocycline
allow for once-daily dosing
 A newly approved tetracycline analog, tigecycline, Is a semisynthetic derivative of
minocycline
Inhibitors of bacterial protein synthesis,
Tetracyclines, contd.
 MOA:
 Tetracyclines enter microorganisms
through cell wall in part by passive diffusion
and in part by an energy-dependent
process of active transport
 Susceptible cells concentrate the drug
intracellularly
 Tetracyclines then bind reversibly to the 30S
subunit of the bacterial ribosome, blocking
the binding of aminoacyl-tRNA to the
acceptor site on the mRNA-ribosome
complex
 This prevents addition of amino acids to
the growing peptide, with subsequent
inhibition of protein synthesis
Inhibitors of bacterial protein synthesis,
Tetracyclines, contd.
 Antimicrobial actions:
 Tetracyclines are active against many G+ve & G-ve bacteria, including anaerobes,
rickettsiae, chlamydiae, mycoplasmas
 Minocycline is usually the most active followed by doxycycline
 They are also active against some protozoa, e.g., amebas
 The antibacterial activities of most tetracyclines are similar except that tetracyclineresistant strains may remain susceptible to doxycycline or minocycline, drugs that
are less rapidly transported by the pump that is responsible for resistance
 Resistance mechanisms :
1. Decreased intracellular accumulation due to either decreased influx or
increased efflux by an active transport protein pump … (the most important)
2. Ribosome protection due to production of proteins that interfere with
tetracycline binding to the ribosome
3. Enzymatic inactivation of tetracyclines
 Resistance is primarily plasmid-mediated and often is inducible
Inhibitors of bacterial protein synthesis,
Tetracyclines, contd.
 Pharmacokinetics
 Substitutions on these rings are responsible for variation in the drugs‘ individual
pharmacokinetics. Thus tetracyclines mainly differ in their absorption after oral
administration and their elimination, causing small differences in their clinical efficacy
 Absorption after oral administration is approximately 30% for chlortetracycline; 60–
70% for tetracycline, oxytetracycline, demeclocycline, and methacycline; and 95–
100% for doxycycline and minocycline
 A portion of an orally administered dose of tetracycline remains in the gut lumen,
modifies intestinal flora, and is excreted in the feces
 Absorption occurs mainly in the upper small intestine and is impaired by food (except
doxycycline and minocycline); by divalent cations (Ca2+, Mg2+, Fe2+) or Al3+; by dairy
products and antacids, which contain multivalent cations, …..so!
 The decreased absorption results from chelation of divalent and trivalent cations
 Tetracyclines are 40–80% bound by plasma proteins. They are distributed widely to
tissues and body fluids except for CSF (levels are 10–25% of those in serum)
 Minocycline reaches very high concentrations in tears and saliva, which makes it useful for
eradication of the meningococcalcarrier state
Inhibitors of bacterial protein synthesis,
Tetracyclines, contd.
 Pharmacokinetics, contd.
 Tetracyclines cross the placenta to reach the fetus and are also excreted in milk. As a
result of chelation with calcium, tetracyclines are bound to—and damage—growing
bones and teeth
 Tetracyclines are excreted mainly in urine (mainly by glomerular filtration) and bile;
Small % of the these drugs are excreted in feces. Some of the drug excreted in bile
is reabsorbed from the intestine (enterohepatic circulation) and contributes to
maintenance of serum levels
 Doxycycline, in contrast to other tetracyclines, is eliminated by nonrenal mechanisms
(excreted in feces), does not accumulate significantly in renal failure, and requires no
dosage adjustment, making it the tetracycline of choice for use in the setting of renal
insufficiency
 Minocycline is recovered from urine and feces in significantly lower amounts than are
the other tetracyclines, and it appears to be metabolized to a considerable extent Its
renal clearance is low. The drug persists in the body long after its administration is
stopped, possibly due to retention in fatty tissues. Nonetheless, its half-life is not
prolonged in patients with hepatic failure